Chimeric antigen receptor T-cell therapy in adults with B-cell acute lymphoblastic leukemia

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapy has transformed treatment paradigms for relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in children and younger adults. We performed a systematic review to investigate the published literature on efficacy and toxicity of CAR-T therapy in adults with r/r B-ALL. We searched MEDLINE, Embase and Cochrane Library for prospective, interventional studies and included published studies of ≥5 patients with median age at enrollment of ≥ 18 years. Risk of bias was assessed using a modified Institute of Health Economics tool. A total of 2566 records were assessed; 16 studies involving 489 patients were included in the final analysis. The mean CR rate was 81% and MRD negative remission rate was 81% at 4 weeks post CAR-T infusion. With median follow-up across studies of 24 months the cumulative 12-month probability of PFS and OS were 37% (95% CI 26-48%) and 57% (95% CI 49-65%), respectively. Relapse occurred in 40.3%; target antigen was retained in 73.2% of relapses. Across studies, any grade of CRS occurred in 82% (95% CI 61-95%) and grade 3 or higher CRS in 27% (95% CI 18-36%). Neurotoxicity of any grade occurred in 34% (95% CI 24-47%) and grade 3 or higher in 14% (95% CI 1-25%). In summary, CAR-T therapy achieves high early remission rates in adults with r/r B-ALL and represents a significant improvement over traditional salvage chemotherapy. Relapses are common and durable response remains a challenge.

A systematic review and meta-analysis of CD22 CAR T-cells alone or in combination with CD19 CAR T-cells

“…Despite these impressive results, around 30% of patients fail to respond to CD19 CAR T-cells, and 36-57% of patients who achieve CR relapse within one year ( 5 , 11 , 15 ). In particular, a subset of relapses are associated with loss of CD19 expression or escape splice variants on malignant cells, with prior studies finding 16-68% of relapses to be CD19-negative ( 11 , 15 , 16 ). Alternate CAR targets for B-cell malignancies are now being explored, including CD22, CD20, CD79b and BAFF-R ( 17 – 23 ).…”

HER2 chimeric antigen receptor T cell immunotherapy is an effective treatment for diffuse intrinsic pontine glioma

“…We know from collective experience with CAR T therapy that targeting a single antigen, both preclinically and clinically, is unlikely to yield a durable long-term remission. Even in CD19-CAR T cell targeting of Acute Lymphoblastic Leukaemia, 40% of patients relapse of which 30% were antigen-negative tumors, 27 and therefore it is certain that combination approaches will require multitargeting of tumor antigens for heterogeneous tumors like DIPG. Within this framework, we hope that our findings can help to enhance and expand the applicability of CAR T cell therapy to benefit H3.3K27M GD2 positive patients, as well as those that are GD2 negative.…”

Measurable residual disease in acute lymphoblastic leukemia: methods and clinical context in adult patients

“…Among children receiving CAR T-cell therapy, real-world datasets have demonstrated improved survival and reduced toxicity following CAR T-cell therapy when administered to patients with lower level/MRD-positive disease, as opposed to patients in full clinical relapse. Although the MRD-negative response rate following CAR T-cell therapy in adult ALL is very high (approximated at 81% in a meta-analysis including 489 adults receiving CAR T-cell therapies across published trials), 74 whether early MRD response to CAR T-cell therapy translates into long-term durable remissions in adult ALL patients remains unclear.…”